Tricarico Domenico, Mele Antonietta, Liss Birgit, Ashcroft Frances M, Lundquist Andrew L, Desai Reshma R, George Alfred L, Conte Camerino Diana
Department of Pharmacobiology, Faculty of Pharmacy, University of Bari, via Orabona no 4, 70120 Bari, Italy.
Neuromuscul Disord. 2008 Jan;18(1):74-80. doi: 10.1016/j.nmd.2007.07.009. Epub 2007 Sep 6.
We investigated on the mechanism responsible for the reduced ATP-sensitive K(+)(K(ATP)) channel activity recorded from skeletal muscle of K(+)-depleted rats. Patch-clamp and gene expression measurements of K(ATP) channel subunits were performed. A down-regulation of the K(ATP) channel subunits Kir6.2(-70%) and SUR2A(-46%) in skeletal muscles of K(+)-depleted rats but no changes in the expression of Kir6.1, SUR1 and SUR2B subunits were observed. A reduced K(ATP) channel currents of -69.5% in K(+)-depleted rats was observed. The Kir6.2/SUR2A-B agonist cromakalim showed similar potency in activating the K(ATP) channels of normokalaemic and K(+)-depleted rats but reduced efficacy in K(+)-depleted rats. The Kir6.2/SUR1-2B agonist diazoxide activated K(ATP) channels in normokalaemic and K(+)-depleted rats with equal potency and efficacy. The down-regulation of the Kir6.2 explains the reduced K(ATP) channel activity in K(+)-depleted rats. The lower expression of SUR2A explains the reduced efficacy of cromakalim; preserved SUR1 expression accounts for the efficacy of diazoxide. Kir6.2/SUR2A deficiency is associated with impaired muscle function in K(+)-depleted rats and in hypoPP.
我们研究了低钾大鼠骨骼肌中ATP敏感性钾通道（K(ATP)通道）活性降低的机制。进行了K(ATP)通道亚基的膜片钳和基因表达测量。观察到低钾大鼠骨骼肌中K(ATP)通道亚基Kir6.2（降低70%）和SUR2A（降低46%）表达下调，但Kir6.1、SUR1和SUR2B亚基的表达没有变化。观察到低钾大鼠的K(ATP)通道电流降低了69.5%。Kir6.2/SUR2A - B激动剂克罗卡林在激活正常血钾和低钾大鼠的K(ATP)通道时显示出相似的效力，但在低钾大鼠中的效能降低。Kir6.2/SUR1 - 2B激动剂二氮嗪以相同的效力和效能激活正常血钾和低钾大鼠的K(ATP)通道。Kir6.2的下调解释了低钾大鼠K(ATP)通道活性的降低。SUR2A的较低表达解释了克罗卡林效能的降低；SUR1表达的保留解释了二氮嗪的效能。Kir6.2/SUR2A缺乏与低钾大鼠和低钾性周期性麻痹患者的肌肉功能受损有关。
